The compound .alpha.-lipoic acid was first isolated by Reed and coworkers as an acetate replacing factor. It is assumed to be substantially insoluble in water, but soluble in organic solvents. .alpha.-lipoic acid is a chiral molecule and is known by a variety of names, including thioctic acid; 1,2-diethylene-3 pentanoic acid; 1,2-diethylene-3 valeric acid; and 6,8-thioctic acid. See Gerreke Biewenga et a., An Overview of Lipoate Chemistry, Lipoic Acid in Health and Disease 1 (1997) (Marcel Dekker). This document, and all other documents cited to herein, is incorporated by reference as if reproduced fully herein.
After being isolated .alpha.-lipoic acid was tentatively classified as a vitamin, but it was later found to be synthesized by animals and humans. The complete enzyme pathway that is responsible for the de novo synthesis has not yet been definitively elucidated. Several studies indicate that octanoate serves as the immediate precursor for the 8-carbon fatty acid chain, and cysteine appears to be the source of sulfur. As a lipoamide, it functions as a cofactor in the multienzyme complexes that catalyze the oxidative decarboxylation of .alpha.-keto acids such as pyruvate, .alpha.-keto glutarate, and branched chain .alpha.-keto acids.
More recently, a great deal of attention has been given to possible antioxidant functions for .alpha.-lipoic acid, and its reduced form, dihydrolipoic acid (DHLA). Lipoate, or its reduced form, DHLA, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, DHLA may exert prooxidant actions to reduction of iron.
The administration of .alpha.-lipoic acid has been shown to be beneficial in a number of oxidative stress models such as ischemia-repercussion injury, diabetes (both .alpha.-lipoic acid and DHLA exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin, and NF-.kappa.B transcription factor.
Lipoate may also have other activities. For example, DHLA has been found in vitro to be an anti-inflammatory agent which at the same time interferes with nitric oxide release from inflammatory macrophages and protects target cells from oxygen radical attack. V. Burkhart, Dihydrolipoic Acid Protects Pancreatic Islet Cells from Inflammatory Attack, Agents Actions 38:60 (1993).
Lipoic acid is a coenzyme for several enzymes. Lipoic acid is a coenzyme for both .alpha.-keto acid dehydrogenase complex enzymes (i.e. pyruvate dehydrogenase complex and .alpha.-keto glutarate dehydrogenase complex), branched chain .alpha.-keto acid dehydrogenase complex, and the glycine cleavage system. In the enzyme system, the body forms a multi-enzyme complex involving lipoic acid, that breaks down molecules of pyruvate produced in earlier metabolism, to form slightly smaller high energy molecules called acetyl-coenzyme A. This results in molecules that can enter into a series of reactions called the citric acid cycle, or Krebs cycle, which finishes the conversion of food into energy. Essentially, lipoic acid stimulates basal glucose transport and has a positive effect on insulin stimulated glucose uptake.